17-oxygenated 4-halo-2-methylene (androst/estr)-4-en-3-ones and intermediates



United States Patent O 17 .OXYGENATED 4 HALO 2 METHYLENE (ANDROST/ESTR) 4 EN 3 ONES AND INTERMEDIATES Ivar Laos, Skokie, Ill., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Filed Feb. 23, 1966, Ser. No. 529,195 8 Claims. (Cl. 260239.55)

This invention relates to 17 oxygenated 4 halo 2- methylene(androst/estr)-4-en-3-ones and intermediates, and to processes for the preparation thereof. More particularly, this invention provides new, useful, and unobvious chemical compounds of the formula HaC in which R represents hydrogen or a lower alkanoyl radical and R represents hydrogen or a lower alkyl or ethynyl radical.

Among the halogens represented by X, especially those of atomic number greater than 9 and less than 53 are preferred, namely, chlorine and bromine. Those skilled in the art will recognize that a lower alkanoyl radical is a radical of the formula CO-lower alkyl the lower alkyl constituent here, as also in the case of the lower alkyl grouping represented by R", being a monovalent, saturated, acyclic, straightor branchedchain, hydrocarbon grouping of empirical formula wherein n represents a positive integer less than 8. Typical lower alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, etc.

The compounds to which this invention relates are useful by reason of their valuable pharmacological prop.- erties. Thus, for example, they counteract the edema and granuloma-formation characteristic of the inflammatory response to tissue insult.

Preparation of the subject compounds proceeds by heating an alcoholic solution of an appropriate epoxide' (R and Z being defined as before) with aqueous formaldehyde in the presence of a mild base such as sodium acetate or sodium bicarbonate to induce a Z-methylene group,

3,352,855 Patented Nov. 14, 1967 whereupon the epoxide linkage is cleaved with an appropriate hydrohalide (X being defined as before) in aqueous acetone solution and the resultant 4,5-halohydrin spontaneously dehydrates to the desired product. Alternatively, the esters of this invention can be prepared by starting with the corresponding epoxy alcohols, introducing the 2-methylene group as aforesaid, then esterifying with pyridine and the appropriate alkanoic acid anhydride or halide before cleaving the epoxide linkage and dehydrating as aforesaid.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for the preparation thereof. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic chemistry that many modifications, both of materials and of methods, can be practiced without departing from the purpose and intent of this disclosure. In the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

EXAMPLE 1 (A) 45,5 3 epoxy 17p hydroxy 2 methyleneandr0stan-3-0ne.-To a solution of 492 parts of 45,55- epoxy-l7fl-hydroxyandrostan-3one in- 7840 parts of methanol at room temperature is consecutively added approximately 2700 parts of aqueous 36% formaldehyde and a solution of 366 parts of sodium acetate in 1470 parts of water. The resultant mixture is heated at the boiling point under reflux for 5 hours, then cooled to room temperature and neutralized with 243 parts of glacial acetic acid. The mixture thusobtained is concentrated to /2 volume by vacuum distillation, and the concentrate is diluted with 7 volumes of ice water. Insoluble solids are filtered ofl, washed with water, and taken up in ether. The ether solution is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation-The residue is 4,13,5{i-epoxy-17,8-hydroxy-2-methyleneandrostan-3-one.

B) 4-chlor0-17,8-hydr0xy-2-methyleneandrost-4-en 3- one.-To a solution of 53 parts of 45,5/8-epoxy-17fi-hydroxy-Z-methyleneandrostan-3one in 8000 parts of acetone at 2025 is added, during 10 minutes, 1190 parts of concentrated hydrochloric acid. The resultant mixture is stirred for 1 hour at room temperatures, then concentrated to the point of incipient precipitation by vacuum distillation. The concentrate is diluted with 5 volumes of ice water and the resultant suspension extracted with dichloromethane. The dichloromethane extract is consecutively Washed with aqueous 3% sodium bicarbonate and water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is 4-chloro-17B-hydroxy-2-methyleneandrost-4-en-3 one, having the formula EXAMPLE 2 (A) 17,3-acezoxy-4Bjfl-epoxy-2 methyleneandrostan- 3-one.-A solution of 51 parts of 4fi,5 8-epoxy-17p-hy- I droxy-Z-methyleneandrostan-3-one in 18 parts of acetic anhydride and 24 parts of pyridine is allowed to stand at room temperatures overnight, whereupon insoluble solids are filtered off, consecutively washed with cold pyridine and ether, and crystallized from acetone to give 17fl-acetoxy-4,8,5B-epoxy-2 methyleneandrostan 3 one melting at 227230.

(B) J 7 acetoay 4-chlore-2-methyleneandrostl-end- 0ne.To a solution of 6 parts of 17fi-acetoxy-4;8,5B- epoxy-Z-methyleneandrostan-3-one in 800-parts of acetone at 20 is added, during approximately minutes, 119 parts of concentrated hydrochloric acid. The resultant mixture is stirred for 45 minutes at room temperatures,

H3O OCOCH:

EXAMPLE 3 17 acetoxy 4 bromo 2 methyleneandrost 4- en-3-one.-To a solution of 12 parts of 17,8-acetoxy-418- 5/3-epoxy-2-methyleneandrostan-3-one in 1920 parts of acetone at 20 is added, during 3 minutes, 337 parts of aqueous 48% hydrogen bromide. The resultant mixture is stirred at room temperatures for 1 hour, whereupon the bulk of the acetone is removed by vacuum distillation and the residual solution diluted with approximately 5 volumes of ice water. The mixture thus obtained is extracted with dichloromethane. The dichloromethane extract is consecutively washed with aqueous 3% sodium bicarbonate and water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The

residual oil, on trituration with ether, crystallizes. The 50 product is 17[3-acetoxy-4-bromo-2-methyleneandrost-4-en- 3-one which, recrystallized from acetone, melts at 169- 171". The product has the formula H3O OCOCHI HaC EXAMPLE 4 volume by vacuum distillation, and the concentrate is partitioned between ice water and ether. The ether phase is separated, washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distil- 5 lation. The residue is 4,8,5B-epoxy-2-methyleneandrostane- 3,17-dione.

(B) 4-011loro-Z-methyIeneandrost-4-ene-3J7 dione. Substitution of 53 parts of 4 3,SfJ-epoxy-Z-methyleneandrostane-3,l7-dione for the 4/9,5 3-epoxy-17/3-hydroxy-2- methyleneandrostan-3-one called for in Example 1B affords, by the procedure there detailed, 4-chloro-2-methyleneandrost-4-ene-3,l7-dione, the formula of which is EXAMPLE 5 (A) 4 3,5f3-ep0xy-17fi-hydr0xy 17a methyl 2 methyleneandr0stan-3-0ne.Substitution of 515 parts of 418, 5fl-epoxy-17fl-hydroxy-17a-methylandrostan-3-one for the 4fl,5/3-epoxyandrostan-3,17-dione called for in Example 4A affords, by the procedure there detailed, 45,5;3-epoxy l7fl-hydroxy-l7a-methyl-Z-methyleneandrostan-3-one.

(B) 4-chl0r0-17 8 hydr0xy-17a-methyl 2 methyleneandrost-4-en-3-onafi$ubstitution of 55 parts of 4 8,518- epoxy-17fl-hydroxy-17a-methyl-2 methyleneandrostan-3- one for the 45,55-epoxy-17,8-hydroxy-2-methyleneandrostan-3-one called for in Example 1B atfords, by the procedure there detailed, 4-ohloro-17B-hydroxy-17a-methyl- 2-methyleneandrost-4-en-3-one, the formula of which is EXAMPLE 6 (A) 4 3,5 3-ep0xy-17;3-hydr0xy 2 methyleneestran-3- one.-To a solution of 36 parts of 46,5;8-epoxy-17B-hydrox'yestran-3-one in 576 parts of ethanol at room temperature is consecutively added 194 parts of aqueous 36% formaldehyde and a solution of 27 parts .of sodium acetate in 108 parts of water. The resultant mixture is heated at the boiling point under reflux for 5 hours, then cooled to room temperature and neutralized with 18 parts of glacial acetic acid. The mixture thus obtained is concentrated to /2 volume by vacuum distillation, and the residue is diluted with 4000 parts of ice water. Insoluble solids are filtered off and taken up in ether. The ether solution is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is 45,5fl-epoxy-l7fl=hydroxy-2-methyleneestran-3-one.

(B) 17/3-acet0xy-4fi,5;3-ep'0xy 2 meflhyleneestran-S- one.A mixture of 19 parts of 45,53-ep0xy-17fl-hydoxy- 2-methyleneestran-3-one, parts of acetic anhydride, and 80 parts of pyridine is allowed to stand at room temperatures overnight, then poured into 1500 parts of ice water. The gummy precipitate thrown down is filtered off and taken up in ether. The ether solution is successively washed with water, 1% hydrochloric acid, water, aqueous 3% sodium bicarbonate, and water; then dried over an- H3O 0000113 (\I H l H20 O: \J

What is claimed is: 1. A compound of the formula wherein R is selected from the group consisting of hydrogen and the methyl radical, X is halogen of atomic number greater than 9 and less than 53, and Z is selected from the group consisting of the carbonyl radical and radicals of the formula in which R is selected from the group consisting of hydrogen and lower alkanoyl radicals of the formula and R" is selected from the group consisting of hydrogen and lower alkyl radicals of the formula n in the last two formulas being a positive integer less than 8.

2. A compound according to claim 1 in which R represents the methyl radical, X represents halogen of atomic number greater than 9 and less than 53, and Z represents the radical O-lower alkanoyl 3. A compound according to claim 1 which is 17 8- acetoxy-4-chloro-2-rnethyleneandrost-4-en-3-one.

4. A compound according to claim 1 which is 17,3- acetoxy-4-bromo-2-methyleneandrost-4-en-3-one.

5. A compound according to claim 1 which is 4-chloro- 2-rnetl1yleneandrost-4-ene-3,17-dione.

6. A compound according to claim 1 which is 4-chl0ro- 17,8-hydroxy-17a methyl 2 methyleneandrost-4-en-3- one.

7. A compound according to claim 1 which is acetoxy-4-chloro-2-methyleneestr-4-en-3-one.

8. A compound of the formula wherein R is selected from the group consisting of hydrogen and the methyl radical and Z is selected from the group consisting of the carbonyl radical and radicals of the formula in which R is selected from the group consisting of hydrogen and lower alkanoyl radicals of the formula and R" is selected from the group consisting of hydrogen and lower alkyl radicals of the formula 2n+1 n in the last two formulas being a positive integer less than 8.

References Cited UNITED STATES PATENTS 3,154,542 10/1964 Bernstein et a1. 260239.55

LEWIS GOTTS, Primary Examiner. I, MESHBESHER Assistant Examiner, 

8. A COMPOUND OF THE FORMULA 